This report reviews a 21st century upgrade to a critical supply item for the manufacture of solid dosage products. It also offers insight into the state of the industry and the development of materials as well as areas of concern regarding contamination and controlBy Blair Scoble
Woven industrial textiles have long been used in a variety of filtration, screening, and separation processes in the manufacturing of pharmaceutical and nutraceutical compounds. Primarily these are found in liquid-solid and gas-solid separation applications in both API and finished pharmaceutical processing. A number of common applications include deliquoring of solids in centrifuges, filter presses or Nutsche filter/dryers, liquid polishing of products or raw materials on filter presses, and product containment in drying systems, particularly fluid bed or tumble style dryers.
All these processes include direct product contact to the filter media surface, many of which are in late stage processes. This report reviews the current state of the industry supplying these products, development of materials used in these separation processes, and the areas of concern regarding contamination and control of these products at the filter manufacturing site as well as in use at the pharmaceutical manufacturer.
A great deal of review and development has occurred in the area of liquid product filtration, primarily in the area of sterilizing filters in the final stages of product development. Strict requirements for these processes, primarily injectable products, have been in place for some time and have been addressed in the cGMP Part 211.72 section dealing primarily with the issue of fiber release and micron retention. Industry groups have worked to review the areas of proper filter use in a variety of applications as well as extractable levels, filter integrity, and absolute vs. nominal filtration ratings. This area has been narrowly focused on cartridge and non-woven pad filters used in this segment of the pharmaceutical industry.
Much less oversight has been applied to woven products historically used in solid dosage product filtration processes. Until recently, many companies handled these filters as supply items with little or no control outside the specific department of use. In fact this is still the norm in many plants, particularly in late stage filtration processes such as final liquid-solid separation and drying of APIs or granulation and coating processes prior to tableting in finished product facilities. Screening applications, although mostly using SS woven wire, is also included as synthetic screen materials become more prominent. Understanding the true nature of these products is critical in the current risk based focus of the world’s regulatory agencies.
Starting With Polymer
At this point, it is worthwhile to understand the development of the industry supplying the woven products to the pharmaceutical industry. Most, if not all, companies supplying the PMI are small business organizations, and many of them are regional owner-operated fabricators. Generally these companies offer a broad range of customized products to a variety of processing industries including PMI. Fabrics are usually purchased in bulk from a multitude of weaving sources domestically and internationally. Fabric production runs in the thousands of yards generally unless smaller quantities are available from standard stock constructions. The previously broad range of available materials has narrowed as weaving mills have reduced offerings for efficiency or mill operations have gone out of business domestically.
Fabric specifications have historically been developed for the larger use process industries where weaving volumes would meet mill minimum runs. These materials were then adapted to other process industries utilizing similar equipment or requiring comparable filtration characteristics. The PMI has not historically shown the volumes of filter media usage equal to other process industries such as mining and refining, food processing, general chemical, or environmental. This has created difficulty in meeting the regulatory requirements, such as compliance to 21CFR, or the specific cleanliness and specification tolerances required by quality-driven companies in the PMI.
Most often, a vague statement of acceptability for the general polymer type has covered the requirements for a declaration of conformity. When looked at more closely, not all yarns specifically meet the exact criteria found in 21CFR177. Polypropylene was considered to be acceptable regardless of polymer formulation. This is mainly due to the inability or unwillingness of most yarn producers to certify to compliance to 21CFR. The volume usage did not warrant the expense. Some are specifically non-compliant due to additive amounts found in the polymer formulation for attributes such as UV inhibiting that are not applicable to most filtration processes.
It is also common for materials to be run with yarns from multiple sources without stringent traceability procedures. Change notification is difficult in these instances with the end user and material purchaser several levels removed from the polymer source. Substitution of yarns is not uncommon with equivalent denier yarns having differing numbers of filament strands as a possibility. This type of change can affect filtration results or cloth life while making traceability virtually impossible.
Cleanliness of Cloth
GMP-procedures required of the pharmaceutical manufacturer state that all product contact areas be cleaned so as not to alter the safety, purity, and efficacy of the drug product. This is normally done by the user with an industrial pre-wash or inside the filter equipment by CIP or rinsing with a process solvent. The extent to which the weaving aids are removed is questionable and generally not known. Quite often the assumption by the user pre-supposes a pristine filter cloth. In subsequent testing of various standard materials, this was found to be an incorrect assumption.
Sample InspectionSeveral industrial textile fabrics commonly used in late-stage filtration applications were tested for extractables using guidelines as recommended in 21CFR177.1520 for compliance of olefin polymers as indirect food additives. In addition, extractables were tested using boiling H2O and EtOH.) All samples were visually inspected for absence of dirt, grease, and other noticeable contaminants. Samples included three common yarn types: staple, multifilament, and monofilament. They represented the most commonly used polymers in polypropylene, polyester, nylon, PTFE, E-CTFE, and PEEK. All materials were considered finished fabrics where some form of post-weaving process was performed to clean and stabilize the fabric. Extractables were listed in total milligrams of extractable, percentage by weight to test sample, milligrams per square meter of fabric, and micrograms per square inch of material. All samples were found to have residual material ranging from 0.03 to 1.57 percent. The extractable levels were for liquid extractables only and did not include solids extractables from polymer breakdown as seen in high solids levels with polypropylene in the N-Hexane extraction. Yarn form and weave construction appeared to play a large role in the percentage of extractable with staple and multifilament fabrics showing the highest level while monofilament fabrics consistently showed the lowest extractable levels. Also, as would be assumed, open plain weave materials showed the lowest levels. This would be due mainly to the high percentage of open area and the smoother, more easily cleaned surface of the single stranded monofilament yarn.
Lacking a specific extractable level specification used by the PMI or regulators, a maximum limit of 1,000 milligrams per square meter was established. This was based on a German directive found in 35 LMBG B 80.30-1 bis 3 EG. In 40 material samples, 15 or more than one-third of the fabrics exceeded this limit in the first test. Based on this, certain fabrics that exceeded the limit were rewashed using a finishing step similar to that used for treating medical device fabrics. Samples were then retested as above and all showed reduction of extractable levels to well below the 1,000 mg level.
Beyond the FabricThe second and equally important side to filter cloth cleanliness is the fabrication technique and manufacturing area. The typical filter cloth manufacturer is similar to a garment producer with cutting and sewing the standard fabrication methods. An audit of the typical plant will show many areas where particulate contamination can occur. Fabric storage is typically on open rolls in a warehouse setting. Initially, rolls may be enclosed in wrapping; however, quite often they are stored unwrapped after initial use. Depending on the environment, they are subject to airborne dust and dirt and often stored open on a shop floor. Plywood and particleboard shelving are also common.
The cutting area is another potential source of loose particulate. Raw cutting of fabrics produces many small fibers that will cling to the cut pieces or tables and can then adhere to subsequent cuttings. Most shops work with a multitude of fiber types and therefore fibers different than those of the actual filter can be present on the finished article. In aggressive chemical environments, these additional polymers can dissolve or end up in product. A review of cutting surfaces will often reveal the use of Masonite and plywood for cutting tables. This is generally considered the standard table surface material for most textile cutting operations.
Second to cutting is the sewing of cut pieces into the various configurations found in pharmaceutical manufacturing operations. As in cutting, a wide variety of materials and types of filtration items will run through the typical filter fabrications shop. Fiber particles from previous jobs will often collect on tabletops, in crevices, and within the internals of the machine. Lubricants used for the moving parts will create, together with the fibers, the potential for contaminants lodging within the filters used in the PMI. The lubricants are generally not reviewed for acceptability of use in pharmaceutical filters. Side and support tables are often constructed of wood or are cardboard lined, offering an additional source of particulate.
Standard fabrication facilities generally do not require the use of good hygiene procedures such as the use of clean smocks and hairnets, regular cleaning of equipment, and prohibition of food and drink in the fabrication area. For common industrial filtration applications, these practices have little bearing. Even cosmetic review of finished product is secondary to fit and function of the filter.
Another area of concern centers on the use of sewing as a method of fabrication. Although historically predominant as the method of manufacturing textile-based filters, the use of sewing threads has created several problems for late-stage pharmaceutical filtering applications. The use of lubricants on the sewing thread offers the same issue of contamination as discussed earlier in the article. This is difficult to avoid in an industrial sewing operation due to several factors. Primary is the ability to avoid constant thread breakage that creates excessive downtime and increases the likelihood of sewing fibers becoming dislodged from the filter. This can create additional contamination issues, and many reworks or investigations of contaminated product have been due to fiber migration coming from the sewing thread or the hairy surface of a spun fabric. This is of particular concern in products made as dry powders that are then dissolved for use in intravenous or subcutaneous drugs.
New developments in fabrication techniques that use alternate methods of bonding the fabric parts are now available. Ultrasonic, RF, and heat welding are being employed to eliminate the need for sewing on many products including centrifuge and Nutsche filter bags, tubular filters, and some dryer bags or sleeves. These bonding techniques have proven reliable in eliminating the contamination issue as well as product loss through needle holes. As products are produced in finer particle sizes, this is a significant issue.
As the FDA and the regulatory agencies around the world revue cGMP procedures and work toward the risk-based approach for the PMI, vendor control through audits and improved specifications will help to elevate the quality of those critical supply items that have a major impact on efficiency and product consistency. Reduction of risk through the proper and early consideration of these items will reduce downtime, rework, and validation time for lower overall operating costs.
Blair Scoble is the pharmaceutical market manager for Sefar Filtration Inc., 111 Calumet St., Depew, NY 14043. He has been in the filtration industry for 32 years and involved with the production and marketing of filtration products to the pharmaceutical manufacturing industry for 20 years. Sefar Filtration is a manufacturer of filtration products and a leader in the development of filtration products. More information is available at 877-481-3626, firstname.lastname@example.org, or www.sefar.us.